The liver is a site at which immune responses often result in tolerance. In allogeneic liver transplantation, infiltration of the transplanted organ by alloreactive T cells is followed by the apoptotic death of these cells. In the immune response to viruses, and in the T cell deletion response of T cell receptor transgenic mice injected with specific antigenic peptide, the disappearance of T cells from the systemic immune system is accompanied by the transient accumulation of large number of apoptotic T cells in the liver. These observations lead them to propose that the liver acts as a graveyard for activated T cells. In the first project period, they have refined this hypothesis by showing that liver accumulation and intrahepatic apoptosis of activated T cells is a property of CD8+ but not CD4+ T cells. The accumulation may be explained by direct trapping of activated CD8+ T cells that pass through the liver. This trapping depends largely on ICAM-1 expressed constitutively in liver. The T cells do not need to receive a Fas-dependent death signal before they go to the liver, but mechanism involves CD1 molecules. To carry this line of investigation forward, they now propose to address whether intrahepatic trapping and apoptosis of CD8+ T cells depends on the expression of specific MHC/peptide complexes in the liver, and if so, whether such expression and the peripheral T cell deletion which results are sufficient to tolerize the systemic immune system. Their preliminary data implicated CD1 in the intrahepatic trapping and apoptosis of T cells, and they will determine whether the involvement of this molecule depends on NK-T cells or is a novel NK-T cell-independent function of CD1. The most obvious effector cell in intrahepatic T cell trapping and destruction is the resident liver macrophage or Kupffer cell, and they will test the importance of Kupffer cells directly. Finally, they have developed a line of transgenic mice with enhanced Fas-dependent T cell apoptosis, and they will use these to address the role of Fas in intrahepatic CD8+ cell killing.